Novel phthalazinones

ABSTRACT

The compounds of formula I in which R1, R2, R3, R4 and R5 have the meanings as given in the description are PDE4/7 inhibitors.

FIELD OF APPLICATION OF THE INVENTION

[0001] The invention relates to novel phthalazinone-derivatives, whichare used in the pharmaceutical industry for the production ofmedicaments.

KNOWN TECHNICAL BACKGROUND

[0002] International Patent Applications WO98/31674, WO99/31071,WO99/31090 and WO99/47505 disclose phthalazinone derivatives havingselective PDE4 inhibitory properties. In the International patentapplication WO01/19818 phthalazinone derivatives with PDE3/4 inhibitoryproperties are disclosed. In the International Patent ApplicationWO94/12461 and In the European Patent Application EP 0 763 5343-aryl-pyridazin-6-one and arylalkyl-diazinone derivatives are describedas selective PDE4 inhibitors.

DESCRIPTION OF THE INVENTION

[0003] It has now been found that the phthalazinone-derivatives, whichare described in greater details below, have surprising and particularlyadvantageous properties.

[0004] The invention thus relates to compounds of formula I

[0005] in which

[0006] R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine,

[0007] R2 is fluorine, bromine or chlorine,

[0008] R3 and R4 are both hydrogen or together form an additional bond,

[0009] R5 is R6, —C_(m)H_(2m)—R7, —C_(n)H_(2n)—C(O)R8, —CH(R9)₂,—C_(p)H_(2p)—Y-Aryl1, R12 or R26, in which

[0010] R6 1 -8C-alkyl, 3-10-cycloalkyl, 3-7C-cycloalkylmethyl,3-7C-alkenyl, 3-7C-alkinyl, phenyl-3-4C-alkenyl, 7-10C-polycycloalkyl,naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, quinazolinyl,quinoxalinyl, cinnolinyl, isoquinolinyt, quinolinyl, indanyl, indazolyl,benzoxazolyl, benzothiazolyl, oxazolyl, thiazolyl, N-methylpiperidyl,tetrahydropyranyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothlophen-3-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4yl-but-1-oxy)-benzoic acid, oran unsubstituted or by R61 and/or R62 substituted phenyl radical, inwhich

[0011] R61 is hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, nitro, cyano, halogen,carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C-alkoxycarbonyl,hydroxy-1-4C-alkyl, amino, mono- or di-1-4C-alkylamino,1-4C-alkylcarbonylamino, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- ordi-1-4C-alkylaminosulfonyl, 4-methylphenylsulfonamido, imidazolyl,tetrazol-5-yl, 2-(1-4C-alkyl)tetrazol-5-yl or 2-benzyl-tetrazol-5-yl and

[0012] R62 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen,

[0013] R7 is hydroxyl, halogen, cyano, nitro, nitroxy(—O—NO₂), carboxyl,carboxyphenyloxy, phenoxy, 1-4C-alkoxy, 3-7C-cycloalkoxy,3-7C-cycloalkylmethoxy, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy,1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, amino, mono- or di-1-4C-alkylamino, or anunsubstituted or by R71 and/or R72 substituted piperidyl, piperazinyl,pyrrolidinyl or morpholinyl radical, where

[0014] R71 is hydroxyl, 1-4C-alkyl, hydroxy-1-4C-alkyl or1-4C-alkoxycarbonyl, and

[0015] R72 is 1-4C-alkyl, carboxyl, aminocarbonyl or1-4C-alkoxycarbonyl,

[0016] R8 is an unsubstituted or by R81 and/or R82 substituted phenyl,naphthyl, phenanthrenyl or anthracenyl radical, in which

[0017] R81 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy,carboxyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, and

[0018] R82 is hydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxywhich is completely or predominantly substituted by fluorine,

[0019] R9 is —C_(q)H_(2q)-phenyl,

[0020] Y is a bond or O (oxygen),

[0021] Aryl1 is an unsubstituted phenyl, naphthyl, pyridyl, pyrazinyi,pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl,isoquinolyl, quinolyl, coumarinyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, benzotriazolyl, N-benzosuccinlmldyl, imidazolyl,pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, a2-(1-4C-alkyl)-thiazol-4-yl radical, or a phenyl radical substituted byR10 and/or R11, in which

[0022] R10 is hydroxyl, halogen, nitro, cyano, 1-4C-alkyl,trifluoromethyl, 1-4C-alkoxy, carboxyl, hydroxycarbonyl-1-4C-alkyl,1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- ordi-1-4C-alkylamino-carbonyl, imidazolyl or tetrazolyl, and

[0023] R11 is hydroxyl, halogen, nitro, 1-4C-alkyl or 1-4C-alkoxy,

[0024] m is an integer from 1 to 8,

[0025] n is an integer from 1 to 4,

[0026] p is an integer from 1 to 6,

[0027] q is an integer from 0 to 2,

[0028] R12 is a radical of formula (a)

[0029] wherein

[0030] R13 is —S(O)₂—R14, —S(O)₂—(CH₂)_(r)—R15, —(CH₂)_(s)—S(O)₂—R16,—C(O)R17, —C(O)—(CH₂)_(r)—R18, —(CH₂)_(s)—C(O)—R19, Hetaryl1, Aryl2 orAryl3-1-4C-alkyl,

[0031] R14 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl, —N(R20)R21,phenyl or phenyl substituted by R22 and/or R23,

[0032] R15 is —N(R20)R21,

[0033] R16 is —N(R20)R21,

[0034] R17 is 1-4C-alkyl, hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl,4-ethyl-piperazin-2,3-dion-1-yl, 2-oxo-imidazolidin-1-yl or —N(R20)R21,

[0035] R18 is —N(R20)R21,

[0036] R19 is —N(R20)R21, phenyl, phenyl substituted by R22 and/or R23and/or R24,

[0037] R20 and R21 are independent from each other hydrogen, 1-7C-alkyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or phenyl, or R20 and R21together and with inclusion of the nitrogen atom to which they arebonded, form a 4-morpholinyl-ring, 1-pyrrolidinyl-ring,1-piperidinyl-ring, 1-hexahydroazepino-ring or a 1-piperazinyl-ring offormula (b)

[0038]  wherein

[0039]  R25 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino,dimethylaminocarbonyimethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethylor tetrahydrofuran-2-ylmethyl,

[0040] R22 is halogen, nitro, cyano, carboxyl, 1-4C-alkyl,trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino, mono-ordi-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino or mono-ordi-1-4C-alkylaminocarbonyl,

[0041] R23 is halogen, amino, nitro, 1-4C-alkyl or 1-4C-alkoxy,

[0042] R24 is halogen,

[0043] Hetaryl1 is pyrimidin-2-yl, thieno-[2,3-d]pyrimidin-4-yl,1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl orfuranyl,

[0044] Aryl2 is pyridyl, phenyl or phenyl substituted by R22 and/or R23,

[0045] Aryl3 is pyrldyl, phenyl, phenyl substituted by R22 and/or R23,2-oxo-2H-chromen-7-yl or 4-(1,2,3-thladiazol4-yl)phenyl,

[0046] r is an integer from 1 to 4,

[0047] s is an integer from 1 to 4,

[0048] R26 is a radical of formula (c)

[0049] wherein

[0050] R27 is —C(O)R28, —(CH₂)_(t)—C(O)R29, —(CH₂)_(u)R30, Aryl4,Hetaryl2, phenylprop-1-en-3-yl or 1-methylpiperidin-4yl,

[0051] R28 hydrogen, 1-4C-alkyl, —OR31, furanyl, indolyl, phenyl,pyridyl, phenyl substituted by R34 and/or R35 or pyridyl substituted byR36 and/or R37,

[0052] R29 is —N(R32)R33,

[0053] R30 is —N(R32)R33, tetrahydrofuranyl or pyridinyl,

[0054] R31 is 1-4C-alkyl,

[0055] R32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl,

[0056] R33 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl,

[0057] or R32 and R33 together and with inclusion of the nitrogen atomto which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-,1-piperidinyl- or 1-hexahydroazepinyl-ring,

[0058] Aryl4 is phenyl, pyridyl, pyrimidinyl, phenyl substituted by R34and/or R35, pyridyl substituted by R36 and/or R37,

[0059] R34 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

[0060] R35 is halogen or 1-4C-alkyl,

[0061] R36 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

[0062] R37 is halogen or 1-4C-alkyl,

[0063] Hetaryl2 is indol4-yl, 2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thladiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl,

[0064] t is an integer from 1 to 4,

[0065] u is an integer from 1 to 4,

[0066] v is an integer from 1 to 2,

[0067] X is —C(O)— or —S(O)₂—,

[0068] and the salts of these compounds, with the proviso that thecompound(cis)-4-(3-Chloro4-methoxy-phenyl)2-cycloheptyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-oneis excluded.

[0069] 1-8C-Alkyl is a straight-chain or branched alkyl radical having 1to 8 carbon atoms. Examples are the octyl, heptyl, isoheptyl(5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl(3,3-dimethylbutyl), neopentyl (2,2-dimethylpropyl), pentyl, isopentyl(3-methylbutyl), 1-ethylpropyl, butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, ethyl and methyl radicals.

[0070] 1-4C-Alkyl is a straight-chain or branched alkyl radical having 1to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl,tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

[0071] 1-4C-Alkoxy is a radical, which, in addition to the oxygen atomcontains a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Alkoxy radicals having 1 to 4 carbon atoms which may be mentionedin this context are, for example, the butoxy, iso-butoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, ethoxy and methoxy radicals.

[0072] 1-4C-Alkoxy which is completely or predominantly substituted byfluorine is, for example, the 2,2,3,3,3-pentafluoropropoxy, theperfluoroethoxy, the 1,2,2-trifluoroethoxy and in particular the1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, thetrifluoromethoxy and the difluoromethoxy radical. “Predominantly” inthis connection means that more than half of the hydrogen atoms of the1-4C-alkoxy groups is replaced by fluorine atoms.

[0073] 1-2C-Alkoxy which is completely or predominantly substituted byfluorine is, for example, the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy and in particular the trifluoromethoxy and thedifluoromethoxy radical.

[0074] 1-8C-Alkoxy is a radical which, in addition to the oxygen atom,contains a straight-chain or branched alkyl radical having 1 to 8 carbonatoms. Alkoxy radicals having 1 to 8 carbon atoms which may be mentionedin this context are, for example, the octyloxy, heptyloxy, isoheptyloxy(5-methylhexyloxy), hexyloxy, isohexyloxy (4-methylpentyloxy),neohexyloxy (3,3-dimethylbutoxy), pentyloxy, isopentyloxy(3-methylbutoxy), neopentyloxy (2,2-dimethylpropoxy), butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and methoxyradicals.

[0075] 3-7C-Cycloalkoxy stands for cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

[0076] 3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy orcycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy andcyclopen-tylmethoxy are preferred.

[0077] 3-10C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.

[0078] 3-7C-Cycloalkylmethyl stands for a methyl radical, which issubstituted by one of the abovementioned 3-7C-cycloalkyl radicals.Examples which may be mentioned are the cyclopropylmethyl, thecyclopentylmethyl and the cyclohexylmethyl radicals.

[0079] 3-7C-Alkenyl is a straight chain or branched alkenyl radicalhaving 3 to 7 carbon atoms. Preferred examples are the 2-butenyl,3-butenyl, 1-propenyl and the 2-propenyl (allyl) radicals.

[0080] 3-7C-Alkinyl is a straight chain or branched alkinyl radicalhaving 3 to 7 carbon atoms. Preferred examples are the 2-penfinyl,2-butinyl, 3-butinyA and the 2-propinyl (propargyl) radicals.

[0081] 7-10C-Polycycloalkyl stands for 7-10C-bicycloalkyl or7-10C-tricycloalkyl radicals, such as for example, bomyl, norbornyl oradamantyl.

[0082] A Phenyl-3-4C-alkenyl radical is, for example, thephenylprop-1-en-3-yl radical.

[0083] Halogen within the meaning of the present invention is bromine,chlorine and fluorine.

[0084] 1-4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1-4Calkyl radicals is bonded. An example is the acetylradical [CH₃C(O)—].

[0085] 1-4C-Alkylcarbonyloxy radicals contain, in addition to the oxygenatom, one of the abovementioned 1-4C-alkylcarbonyl radicals. An exampleis the acetoxy radical [CH₃C(O)—O—].

[0086] A 1-4C-Alkylcarbonylamino radical is, for example, the acetamidoradical [—NH—C(O)—CH₃].

[0087] 1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. Examples are theethoxycarbonyl [CH₃CH₂O—C(O)—] and the methoxycarbonyl [CH₃O—C(O)—]radicals.

[0088] Mono- or Di-1-4C-alkylaminocarbonyl radicals are, for example,the methylaminocarbonyl, the dimethylaminocarbonyl and thediethylaminocarbonyl radicals.

[0089] Mono- or Di-1-4C-alkylamino radicals are, for example, themethylamino, the dimethylamino and the diethylamino radicals.

[0090] Mono- or Di-1-4C-alkylaminosulfonyl stands for a sulfonyl groupto which one of the abovementioned mono- or di-1-4C-alkylamino radicalsis bonded. Examples which may be mentioned are the methylaminosulfonyl,the dimethylaminosulfonyl and the ethylaminosulfonyl radical.

[0091] Hydroxy-1-4C-alkyl stands for one of the abovementloned1-4C-alkyl radicals which is substituted by hydroxyl. Examples which maybe mentioned are the hydroxymethyl radical, the 2-hydroxyethyl radicalor the 3-hydroxypropyl radical.

[0092] Hydroxycarbonyl-1-4C-alkyl radicals are, for example, thehydroxycarbonylmethyl [—CH₂C(O)OH] and the hydroxycarbonylethyl[—CH₂CH₂C(O)OH] radicals.

[0093] If R3 and R4 together form an additional bond, then the carbonatoms to which R3 and R4 are attached are linked to one another via adouble bond.

[0094] The groups —C_(m)H_(m)—, —C_(n)H_(2n)—, —C_(p)H_(2p)— and—C_(q)H_(2q)— can be straight chain or branched groups. Examples whichmay be mentioned for the —C_(m)H_(2m)— group are the octylene,heptylene, isoheptylene (2-methylhexylene), hexylene, isohexylene(2-methylpentylene), neohexylene (2,2-dimethylbutylene), butylene,isobutylene, sec-butylene, tert-butylene, propylene, isopropylene,ethylene, 1-methylmethylene and the methylene group.

[0095] Examples which may be mentioned for the —C_(p)H_(2p)— group arethe hexylene, isohexylene (2-methylpentylene), neohexylene(2,2-dimethylbutylene), butylene, isobutylene, sec-butylene,tert-butylene, propylene, isopropylene, ethylene, 1-methylmethylene andthe methylene group.

[0096] Examples which may be mentioned for the —C_(m)H_(2m)— group arethe butylene, isobutylene, sec-butylene, tert-butylene, propylene,isopropylene, ethylene, 1-methylmethylene and the methylene group.

[0097] Examples which may be mentioned for the —C_(q)H_(2q)— group arethe ethylene, 1 -methylmethylene and the methylene group. The group—C_(q)H_(2q)— represents a covalent bond in case of q is 0 (zero).

[0098] Aza-heterocyles which are a component (=Aryl1) of the group ofsubstituents defined as —C_(p)H_(2p)-Aryl1 and contain the grouping —NH—(imino), such as for example, pyrrole, imidazole, benzimidazole,benzotriazole or benzosuccinimide, are preferably bonded via theirimino-nitrogen to the above defined —C_(p)H_(2p)— group.

[0099] Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-soluble and water-insolubleacid addition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

[0100] On the other hand, salts with bases are—depending onsubstitution—also suitable. As examples of salts with bases arementioned the lithium, sodium, potassium, calcium, aluminium, magnesium,titanium, ammonium, meglumine or guanidinium salts, here, too, the basesbeing employed in salt preparation in an equimolar quantitative ratio orone differing therefrom.

[0101] Pharmacologically intolerable salts, which can be obtained, forexample, as process products during the preparation of the compoundsaccording to the invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled In the art.

[0102] According to experts knowledge the compounds of the invention aswell as their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

[0103] Compounds of formula I which are to be emphasized are those inwhich

[0104] R1 is methoxy or ethoxy,

[0105] R2 is chlorine, bromine or fluorine

[0106] R3 and R4 together form an additional bond,

[0107] R5 is R6, —C_(m)H_(2m)—R7, —C_(p)H_(2p)—Y-Aryl1, R12 or R26 inwhich

[0108] R6 3-6C-cycloalkyl, 3-7C-cycloalkylmethyl, quinoxalinyl,indazolyl, benzothiazolyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,3-thiophen-2-yl[1,2,4]-thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)-benzoic acid,or an unsubstituted or by R61 substituted phenyl radical, in which

[0109] R61 is 1-4C-alkyl, 1-4C-alkoxy, carboxyl or 1-4C-alkoxycarbonyl,

[0110] R7 is carboxyphenyloxy,

[0111] Y is a bond,

[0112] Aryl1 is imidazolyl,

[0113] m is an integer from 1 to 4,

[0114] p is an integer from 1 to 4,

[0115] R12 is a radical of formula (a)

[0116] wherein

[0117] R13 is —S(O)₂—R14, —C(O)R17 or Aryl3-1-4C-alkyl,

[0118] R14 is phenyl or phenyl substituted by R22,

[0119] R17 is 1-4C-alkyl, 2-oxo-imidazolidin-1-yl or —N(R20)R21,

[0120] R20 and R21 are independent from each other 1-7C-alkyl, or R20and R21 together and with inclusion of the nitrogen atom to which theyare bonded, form a 4-morpholinyt, 1-pyrrolidinyl-, 1-piperidinyl- or1-hexahydroazepino-ring,

[0121] R22 is 1-4C-alkyl,

[0122] Aryl3 is pyridyl,

[0123] R26 is a radical of formula (c)

[0124] wherein

[0125] R27 is —(CH₂)_(u)R30,

[0126] R30 is —N(R32)R33,

[0127] R32 is 1 -4C-alkyl,

[0128] R33 is 1-4C-alkyl,

[0129] or R32 and R33 together and with Inclusion of the nitrogen atomto which they are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-,1-piperidinyl- or 1-hexahydroazepinyl-ring,

[0130] u is an integer from 1 to 4,

[0131] v is 1,

[0132] X is —C(O)—,

[0133] and the salts of these compounds.

[0134] Compounds of formula I which are particularly to be emphasizedare those in which

[0135] R1 is methoxy or ethoxy,

[0136] R2 is chlorine, bromine or fluorine,

[0137] R3 and R4 together form an additional bond,

[0138] R5 is 1-(morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethylypiperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3yl, benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid,4-hydroxycarbonylphenyl or1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl,

[0139] and the salts of these compounds.

[0140] Preferred compounds of formula I are those in which

[0141] R1 is methoxy or ethoxy,

[0142] R2 is chlorine,

[0143] R3 and R4 together form an additional bond,

[0144] R5 is 1-(morpholin-4-yl-methanoyl)-piperidinyl,1-(toluene-4-sulfonyl)-piperidinyl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidinyl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)benzoic acid,4-hydroxycarbonylphenyl or1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl,

[0145] and the salts of these compounds.

[0146] Further preferred compounds of formula I are

[0147](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(1-morpholin-4yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0148](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0149](cis)-2-(1-Acetyl-piperidin-4-yl)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0150](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0151](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0152](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(6-methyl-3-trifluoromethyl-pyridin-2-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0153](cis)-2-Benzothiazol-6-yl-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0154](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0155](cis)-4-(3-Chloro4-methoxy-phenyl)-2-(1H-indazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0156](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-cyclopentyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0157](cis)-4-(3-Chloro-4-methoxy-phenyl)2-(4-imidazol-1-yl-butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0158](cis)-4-{4-[4-(3-Chloro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-butoxy}-benzoicacid,

[0159](cis)-4-[4-(3-Fluoro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-benzoicacid,

[0160](cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzoicacid,

[0161](cis)-4-{4-(3-bromo-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}benzoicacid,

[0162](cis)-4-(3-chloro-4-methoxy-phenyl)-2-quinoxalin-2-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0163](cis)-4-(3-Chloro-4-methoxy-phenyl)2-(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0164](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0165](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,1-dioxo-tetrahydro-1l(6)-thiophen-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0166](cis)-4-(3-Chloro-4ethoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0167](cis)-4-(3Chloro-4-methoxy-phenyl)-2-phenyl-4a25,8,8a-tetrahydro-2H-phthalazin-1-one,

[0168](cis)-4-(3-Chloro-4-methoxy-phenyl)-2-{1-[1-(2-oxo-imidazolidin-1-yl)-methanoyl]-piperidine-4-yl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,

[0169] and the salts of these compounds.

[0170] A special embodiment of the compounds of the present inventioninclude those compounds of formula I in which R1 is 1-2C-alkoxy, R2 ischlorine, R3 and R4 together form an additional bond and R5 is R6.

[0171] Another special embodiment of the compounds of the presentInvention include those compounds of formula I in which R1 is1-2C-alkoxy, R2 is chlorine, R3 and R4 together form an additional bondand R5 is —C_(m)H_(2m)—R7.

[0172] A further special embodiment of the compounds of the presentInvention Include those compounds of formula I in which R1 is1-2C-alkoxy, R2 is chlorine, R3 and R4 together form an additional bondand R5 is —C_(p)H_(2p)—Y-Aryl1.

[0173] Still another special embodiment of the compounds of the presentinvention include those compounds of formula I in which R1 is1-2C-alkoxy, R2 is chlorine, R3 and R4 together form an additional bondand R5 is R12.

[0174] Yet another special embodiment of the compounds of the presentInvention include those compounds of formula I in which R1 is1-2C-alkoxy, R2 is chlorine, R3 and R4 together form an additional bondand R5 is R26.

[0175] The compounds of formula I are chiral compounds. Chiral centersexist in the compounds of formula I in the positions 4a and 8a.

[0176] Therefore the invention includes all conceivable purediastereomers and pure enantiomers of the compounds of formula I, aswell as all mixtures thereof independent from the ratio, including theracemates. Preferred are those compounds of formula I, in which thehydrogen atoms in the positions 4a and 8a are cis-configurated.Especially preferred in this connection are those compounds, in whichthe absolute configuration (according to the rules of Cahn, Ingold andPrelog) is S in the position 4a and R in the position 8a.

[0177] Racemates can be split up into the corresponding enanflomers bymethods known by a person skilled in the art. Preferably the racemicmixtures are separated into two diastereomers during the preparationwith the help of an optical active separation agent on the stage of thecyclohexanecarboxylic acids or the 1,2,3,6-tetrahydrobenzoic acids (forexample, starting compounds A5 and A6). As separation agents may bementioned, for example, optical active amines such as the (+)- and(−)-forms of 1-phenylethylamine[(R)-(+)-1-phenylethylamine=D-α-methylbenzylamine; or(S)-(−)-1-phenylethylamine=L-α-methylbenzylamine), ephedrine, theoptical active alkaloids quinine, cinchonine, cinchonidine and brucine.

[0178] The compounds according to the invention can be prepared, forexample, as described in Reaction scheme 1, 2 or 3.

[0179] Compounds, in which R5 stands for R12 preferably preparedaccording to reaction scheme 2.

[0180] Compounds, in which R5 stands for R26 are preferably preparedaccording to reaction scheme 3.

[0181] Suitably, the conversions are carried out analogous to methodswhich are familiar per se to the person skilled in the art, for example,in the manner which is described in the following examples.

[0182] The substances according to the invention are isolated andpurified in a manner known per se, e.g. by distilling off the solvent invacuo and recrystallising the residue obtained from a suitable solventor subjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

[0183] Salts are obtained by dissolving the free compound in a suitablesolvent (for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedinto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

[0184] The following examples illustrate the invention in greaterdetail, without restricting it. As well, further compounds of formula I,of which the preparation is explicitly not described, can be prepared inan analogous way or in a way which is known by a person skilled in theart using customary preparation methods.

[0185] The compounds, which are mentioned in the examples as well astheir salts are preferred compounds of the invention.

EXAMPLES Final Products

[0186] 1.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0187] A solution of 1.0 g of intermediate product A1 and 1.0 g ofmorpholine-4-carbonyl chloride in 50 ml of pyridine is stirred at RT for18 h after which the mixture is evaporated. The residue is partitionedbetween aqueous sodium carbonate and dichloromethane. Thedichloromethane layer is dried over magnesium sulfate and evaporated.The compound is crystailised from diethyl ether. M. p. 185-186° C.

[0188] 2.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0189] A solution of 1.0 g of intermediate product A1 and 1.0 g ofp-toluenesulfonyl chloride in 50 ml of pyridine is stirred at RT for 18h after which the mixture is evaporated. The residue is partitionedbetween aqueous sodium carbonate and dichloromethane. Thedichloromethane layer is dried over magnesium sulfate and evaporated.Crystallised from a mixture of ethyl acetate and petroleum ether (60-80°C). M. p. 198-199° C.

[0190] 3.(cis)-2-(1-Acetyl-piperidin-4-yl)-4-(3-chloro-4-methoxy-phenyl)-4a,5.8,8a-tetrahydro-2H-phthalazin-1-one

[0191] A solution of 1.0 g of intermediate product A1 and 1.0 g ofacetic anhydride in 50 ml of pyridine is stirred at RT for 18 h afterwhich the mixture is evaporated. The residue is partitioned betweenaqueous sodium carbonate and dichloromethane. The dichloromethane layeris dried over magnesium sulfate and evaporated. Crystallised from ethylacetate. M. p. 206-208° C.

[0192] 4.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0193] A mixture of 1.0 g of intermediate product A1, 1.0 g of4-picolylchloride hydrochloride and 1.0 g of potassium carbonate in 20ml of dimethylformamide is stirred for 18 h at RT after which 100 ml ofwater is added to the reaction mixture. The mixture is extracted withdiethyl ether. The ether solution is dried over magnesium sulfate. Afterthe addition of a saturated solution of hydrochloric acid in ether, thecompound precipitated. M. p. 244° C. (decomposition).

[0194] 5.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onedihydrochloride

[0195] A mixture of 2 mmol of intermediate product A2, 2 mmol of1-(2-dimethylaminoethyl)-piperazine and 3 mmol of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 30 ml ofdimethylformamide is stirred for 18 h, after which the mixture is pooredinto aqueous sodium carbonate. This mixture is extracted with diethylether and the extract is dried over magnesium sulfate. Addition of asolution of hydrochloric acid in ether causes precipitation of the titlecompound. M. p.198-201° C.

[0196] 6.(cis)-4-(3-Chloro-4-methoxy-phenyl-2-(6-methyl-3-trifluoromethyl-pyridin-2-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0197] A solution of 12 mmol of6-methyl4trifluoromethyl-pyridin-2-yl)hydrazine, 10 mmol of startingcompound A6 and 1 g of pyridine hydrochloride in 50 ml of pyridine isrefluxed for 18 h after which the solvent is evaporated. The residue isdissolved in dichloromethane and this solution is washed with 1Nhydrochloric acid. The organic phase is dried over magnesium sulfate andevaporated. The residue is crystallised from diethyl ether. M. p.156-157° C.

[0198] 7.(cis)-2-Benzothiazol-6-yl-4-(3-chloro-4-methoxy-phenyl)-4a,8,8a-tetrahydro-2H-phthalazin-1-one

[0199] A solution of 12 mmol of benzothiazol-6-ylhydrazine, 10 mmol ofstarting compound A6 and 1 g of pyridine hydrochloride in 50 ml ofpyridine is refluxed for 18 h after which the solvent is evaporated. Theresidue is dissolved in dichloromethane and this solution is washed with1N hydrochloric acid. The organic phase is dried over magnesium sulfateand evaporated. The residue is crystallised from diethyl ether. M. p.156-157° C.

[0200] 8.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0201] A solution of 12 mmol of 5-hydrazino-3H-isobenzofuran-1-one, 10mmol of starting compound A6 and 1 g of pyridine hydrochloride in 50 mlof pyridine is refluxed for 18 h after which the solvent is evaporated.The residue is dissolved in dichloromethane and this solution is washedwith 1N hydrochloric acid. The organic phase is dried over magnesiumsulfate and evaporated. The residue is crystallised from diethyl ether.M. p. 212-213° C.

[0202] 9.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1H-indazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0203] A solution of 12 mmol of 1H-indazol-5-ylhydrazine, 10 mmol ofstarting compound A6 and 1 g of pyridine hydrochloride in 50 ml ofpyridine is refluxed for 18 h after which the solvent is evaporated.After evaporating the pyridine, the residue is dissolved in ethylacetate and washed with aqueous sodium carbonate. The solvent is driedover magnesium sulfate and evaporated. The residue is dissolved in ethylacetate and to this solution, a solution of hydrochloric acid in etheris added. The precipitate is filtered off and dried. M p. 196-197° C.

[0204] 10.(cis)-4-(3Chloro-4-methoxy-phenyl)-2-cyclopentyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0205] 12 mmol of sodium hydride is added to a solution of 10 mmol ofintermediate product A3 in 50 ml of DMF. The resulting mixture isstirred for 30 min after which 10 mmol of chlorocyclopentane is added.The resulting mixture is stirred for 1 h and subsequently poured intowater. The precipitate is filtered off and crystallised from methanol.M. p. 201-202° C.

[0206] 11.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-imidazol-1-yl-butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-onehydrochloride

[0207] A mixture of 5 mmol of intermediate product A4 and 20 mmol ofimidazole in 20 ml of DMF is stirred for 18 h at RT after which thesolution is poured into aqueous sodium carbonate. This solution isextracted with diethyl ether. After drying over magnesium sulfate, asolution of hydrochloric acid in ether is added. The precipitate isfiltered off and dried. M. p. 217-219° C.

[0208] 12.(cis)-4-{4-[4-(3-Chloro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-butoxy}benzoicacid

[0209] A solution of 5 mmol of intermediate product A4, 5 mmol of4-hydroxybenzoic acid and 20 mmol of potassium carbonate in 50 ml of DMFis stirred for 18 h at RT after which the solution is poured into water.This aqueous solution is washed with diethyl ether twice andsubsequently acidified with hydrochloric acid. The acidified solution isextracted with diethyl ether (3×) and the organic solution is dried overmagnesium sulfate. The compound crystallised on concentrating underreduced pressure. M. p. 169-171° C.

[0210] 13.(cis)-4-[4-(3-Fluoro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-benzoicacid

[0211] A solution of 12 mmol of 4hydrazinobenzoic acid, 10 mmol ofstarting compound A5 and 1 g of pyridine hydrochloride in 50 ml ofpyridine is refluxed for 18 h after which the solvent is evaporated. Theresidue is dissolved in dichloromethane and this solution is washed with1N hydrochloric acid. The organic phase is dried over magnesium sulfateand evaporated. The residue is crystallised from diethyl ether. M p.201-203° C.

[0212] 14.(cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}-benzoicacid

[0213] A solution of 8 g of starting compound A6 and 8 g of4-hydrazinobenzoic acid in a mixture of 100 ml of 1-propanol and 5 ml oftriethylamine is refluxed for 18 h. After evaporating the solvent, theresidue is partitioned between diluted hydrochloric acid anddichloromethane. The organic layer is dried over magnesium sulfate andevaporated. The residue is purified by chromatography (ethyl acetate).Crystallisation from diethyl ether. M. p. 222-224° C.

[0214] 15.(cis)-4-{4-(3-bromo-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}-benzoicacid

[0215] Prepared from 4-hydrazinobenzoic acid and starting compound A10as described for compound 13.

[0216] M. p. 231-234° C.

[0217] 16.(cis)-4-(3-chloro-4-methoxy-phenyl)-2-quinoxalin-2-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0218] Prepared from quinoxalin-2-yl-hydrazine and starting compound A6as described for compound 7.

[0219] M. p. 172-174° C.

[0220] 17.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0221] Prepared from(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-hydrazine and startingcompound A6 as described for compound 7. M. p. 217-219° C.

[0222] 18.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0223] Prepared from (3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)-hydrazineand starting compound A6 as described for compound 7. M. p. 254-256° C.

[0224] 19. (cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,1-dioxo-tetrahydro-1l⁶-thiophen-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0225] Prepared from (1,1-dioxo-tetrahydro-1l⁶-thiophen-3-yl)-hydrazineand starting compound A6 as described for compound 7. M. p. 181-184° C

[0226] 20. (cis)-4o-3-Chloro -4nethoxy- phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0227] Prepared from phenythydrazine and starting compound A11 asdescribed for compound 7. M. p. 161-162° C.

[0228] 21.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0229] Prepared from phenylhydrazine and starting compound A6 asdescribed for compound 7. M. p. 151-152° C.

[0230] 22.cis-4-(3-Chloro-4-methoxy-phenyl)-2-{1-[1-(2-oxo-imidazolidin-1-yl)-methanoyl]-piperidin-4-yl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0231] Prepared from intermediate product A1 and2-oxo-imidazolidine-1-carbonyl chloride as described for compound 1. M.p. 216-218° C.

[0232] Starting Compounds and Intermediate Products:

[0233] A1.(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-piperidin-4-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0234] A solution of 50 mmol of starting compound A6, 55 mmol ofpiperidin-4-yl-hydrazine dihydrochloride (intermediate product A7) and100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h.After cooling to RT, the precipitate is filtered off and dried. M. p.268-270° C.

[0235] A2.(cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}-benzoicacid

[0236] A solution of 8 g of starting compound A6 and 8 g of4-hydrazinobenzoic acid in a mixture of 100 ml of 1-propanol and 5 ml oftriethylamine is refluxed for 18 h. After evaporating the solvent, theresidue is partitioned between diluted hydrochloric acid anddichloromethane. The organic layer is dried over magnesium sulfate andevaporated. The residue is purified by chromatography (ethyl acetate).Crystallisation from diethyl ether. M. p. 222-224° C.

[0237] A3.(cis)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8.8a-tetrahydro-2H-phthalazin-1-one

[0238] A solution of 50 mmol of starting compound A6 and 0.1 mol ofhydrazine hydrate in 100 ml of ethanol is refluxed for 5 h. On coolingto RT the compound precipitated. M. p. 201-204° C.

[0239] A4.(cis)-2-(4-bromo-butyl)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one

[0240] 12 mmol of sodium hydride is added to a solution of 10 mmol ofintermediate product A3 in 50 ml of DMF. The resulting mixture isstirred for 30 min after which 50 mmol of 1,4-dibrombutane is added. Theresulting mixture is stirred for 1 h and subsequently poured into water.Purified by chromatography (ethyl acetate:hexane/1:4) and crystallisedfrom hexane. M. p. 109-111° C.

[0241] A5. (cis)-2-(3-fluoro-4-methoxybenzoyl)-1,2,3,6-tetrahydrobenzoicacid

[0242] Prepared analogously to starting compound A6 as described inWO99/47505 using 2-fluoroanisole instead of 2-chloroanisole. M. p.185-187° C.

[0243] A6. (cis)-2-(3-chloro-4methoxybenzoyl)-1,2,3,6-tetrahydrobenzolcacid

[0244] Prepared as described in WO99/47505.

[0245] A7. Piperidin-4-yl-hydrazine dihydrochloride

[0246] A mixture of 0.1 mole of4-(N′-tert-Butoxycarbonyl-hydrazinoypiperidine-1-carboxylic acidtert-butyl ester (intermediate product A8) and 150 ml of concentratedhydrochloric acid is heated at 90° C. for 60 min after which the clearsolution is evaporated. The residue is washed with tetrahydrofurane,filtered off and dried under vacuum. M. p. 256-259° C.

[0247] A8. 4-(N′-tert-Butoxycarbonyl-hydrazino)-piperidine-1-carboxylicacid tert-butyl ester

[0248] 150 ml of a solution of borohydride in tertahydrofurane (1.0mol/l) is slowly added to a solution of 0.12 mole of4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylic acidtert-butyl ester (intermediate product A9) in 100 ml of drytetrahydrofurane. After complete addition, the mixture is stirred foranother 30 min after which a 100 ml of water is added to destroy theexcess of borohydride. Subsequently the tetrahydrofurane is evaporatedand the resulting aqeous solution extracted with diethyl ether. Afterdrying the solvent over magnesium sulfate, the ether is evaporated. M.p.112-115° C.

[0249] A9. 4-(tert-Butoxycarbonyl-hydrazono)-piperidine-1-carboxylicacid tert-butyl ester

[0250] A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (commercially available) and 0.15 mole oftert-butylcarbazate in 250 ml of hexane is stirred for 18 h at RT. Theprecipitate is filtered off and dried under vacuum. M. p. 172-174° C.

[0251] A10. (cis)-2-(3-bromo-4-methoxybenzoyl)-1,2,3,6-tetrahydrobenzoicacid

[0252] Prepared analogously to starting compound A6 as described inWO99/47505 using 2-bromoanisole instead of 2-chloroanisole. M. p.201-204 ° C.

[0253] A11. (cis)-2-(3-chloro-4-ethoxybenzoyl)-1,2,3.6-tetrahydrobenzoicacid

[0254] Prepared analogously to starting compound A6 as described inWO99/47505 using 1-chloro-2-ethoxybenzene instead of 2-chloroanisole. M.p.123-125° C.

Commercial Utility

[0255] The second messenger cyclic AMP (CAMP) is well-known forinhibiting inflammatory and immunocompetent cells. The PDE4 isoenzyme isbroadly expressed in cells involved in the initiation and propagation ofinflammatory diseases (H Tenor and C Schudt, in “PhosphodiesteraseInhibitors”, 21-40, “The Handbook of Immunopharmacology”, AcademicPress, 1996), and its inhibition leads to an increase of theintracellular cAMP concentration and thus to the inhibition of cellularactivation (J E Souness et al., Immunopharnacology 47: 127-162, 2000).

[0256] The antiinflammatory potential of PDE4 inhibitors in vivo invarious animal models has been described (M M Teixeira, TiPS 18:164-170, 1997). For the investigation of PDE4 inhibition on the cellularlevel (in vitro), a large variety of proinflammatory responses can bemeasured. Examples are the superoxide production of neutrophilic (CSchudt et al., Arch Pharmacol 344: 682-690, 1991) or eosinophilic (AHatzelmann et al., Brit J Pharmacol 114: 821-831, 1995) granulocytes,which can be measured as luminol-enhanced chemiluminescence, or thesynthesis of tumor necrosis factor-α in monocytes, macrophages ordendritic cells (Gantner et al., Brit J Pharmacol 121: 221-231, 1997,and Pulmonary Pharmacol Therap 12: 377-386, 1999). In addition, theimmunomodulatory potential of PDE4 inhibitors is evident from theinhibition of T-cell responses like cytokine synthesis or proliferation(DM Essayan, Biochem Pharmacol 57: 965-973, 1999). Substances whichinhibit the secretion of the afore-mentioned proinflammatory mediatorsare those which inhibit PDE4. PDE4 inhibition by the compounds accordingto the invention is thus a central indicator for the suppression ofinflammatory processes.

[0257] Of the 11 phosphodiesterase (PDE) isoenzymes which are presentlyknown, PDE7 was described for the first time, as HCP1 (“high affinitycAMP-specific PDE”), in 1993 (Michaeli T, Bloom T J, Martins T, LoughneyK, Ferguson K, Riggs M, Rodgers L, Beavo J A and Wigler M, Isolation andcharacterization of a previously undetected human cAMP phosphodiesteraseby complementation of cAMP phosphodiesterase-deficient Saccharomycescerevisiae, J Biol Chem 268: 12925-12932, 1993). According to today'snomenclature, HCP1 is human PDE7A1; in addition to this, another humansplicing variant of the same gene (PDE7A 2) (Han P, Zhu X and MichaeliT, Altemative splicing of the high affinity cAMP-specificphosphodiesterase (PDE7A) mRNA in human skeletal muscle and heart. JBiol Chem 272: 16152-16157, 1997) and a second human PDE7 gene (PDE7B)(Sasaki T, Kotera J, Yuasa K and Omori K, Identification of human PDE7B,a cAMP-specific phosphodiesterase Biochem Biophys Res Commun 271:575-583, 2000) were described in the subsequent years. Individualrepresentatives of the PDE7 isoenzyme are characterized by beingparticularly prominently expressed in specific areas of the brain(putamen, caudate nucleus), in skeletal muscle, in leukaemic T celllines and in naive CD4+ T cells. The induction of PDE7 has beendescribed as being an essential prerequisite for activating T cells (LiL, Yee C and Beavo J A, CD3- and CD28-dependent induction of PDE7required for T cell activation. Science 283: 848-851, 1999).

[0258] The compounds according to the invention have usefulpharmacological properties which make them industrially utilizable. Asselective cyclic nucleotide phosphodiesterase (PDE) inhibitors(specifically of type 4 and 7), they are suitable on the one hand asbronchial therapeutics (for the treatment of airway obstructions onaccount of their dilating action but also on account of theirrespiratory rate- or respiratory drive-increasing action) and for theremoval of erectile dysfunction on account of their vascular dilatingaction, but on the other hand especially for the treatment of disorders,in particular of an inflammatory nature, e.g. of the airways (asthmaprophylaxis), of the skin, of the intestine, of the eyes, of the CNS andof the joints, which are mediated by mediators such as histamine, PAF(platelet-activating factor), arachidonic acid derivatives such asleukotrienes and prostaglandins, cytokines, T-cells, interleukins,chemokines, alpha-, beta- and gamma-interferon, tumor necrosis factor(TNF) or oxygen free radicals and proteases.

[0259] On account of their PDE-inhibiting properties, the compoundsaccording to the invention can be employed in human and veterinarymedicine as therapeutics, where they can be used, for example, for thetreatment and prophylaxis of the following Illnesses: acute and chronic(in particular inflammatory and allergen-induced) airway disorders ofvarying origin (bronchitis, allergic bronchitis, bronchial asthma,emphysema, COPD); dermatoses (especially of proliferative, inflammatoryand allergic type) such as psoriasis (vulgaris), toxic and allergiccontact eczema, atopic eczema, seborrhoeic eczema, Lichen simplex,sunburn, pruritus in the anogenital area, alopecia areata, hypertrophicscars, discoid lupus erythematosus, follicular and widespreadpyodermias, endogenous and exogenous acne, acne rosacea and otherproliferative, inflammatory and allergic skin disorders; disorders whichare based on an excessive release of TNF and leukotrienes, for exampledisorders of the arthritis type (rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic conditions), disordersof the immune system (AIDS, multiple sclerosis), graft versus hostreaction, allograft rejections, types of shock (septic shock, endotoxinshock, gram-negative sepsis, toxic shock syndrome and ARDS (adultrespiratory distress syndrome)) and also generalized inflammations inthe gastrointestinal region (Crohn's disease and ulcerative coltis);disorders which are based on allergic and/or chronic, immunologicalfalse reactions in the region of the upper airways (pharynx, nose) andthe adjacent regions (paranasal sinuses, eyes), such as allergicrhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctiyltisand also nasal polyps; but also disorders of the heart which can betreated by PDE inhibitors, such as cardiac insufficiency, or disorderswhich can be treated on account of the tissue-relaxant action of the PDEinhibitors, such as, for example, erectile dysfunction or colics of thekidneys and of the ureters in connection with kidney stones. Inaddition, the compounds of the invention are useful in the treatment ofdiabetes insipidus and conditions associated with cerebral metabolicinhibition, such as cerebral senility, senile dementia (Alzheimer'sdisease), memory impairment associated with Parkinson's disease ormultiinfarct dementia; and also illnesses of the central nervous system,such as depressions or arteriosclerotic dementia.

[0260] Particularly on account of their PDE7-inhibiting properties, thecompounds according to the invention are suitable for treating T-cellmediated diseases of inflammatory nature, for example of the kidney(glomerulonephritis) or of the pancreas (autoimmune diabetes) and,furthermore, for inhibiting the degenerative proliferation of T cells invarious forms of T cell leukaemia. In addition, the said compounds areof potential value in treating certain diseases of the brain (such asepilepsy) and of the skeletal muscle (such as muscular atrophy).

[0261] The compounds according to the invention are distinguished by alow toxicity, a good enteral absorption (high bioavailability), a largetherapeutic breadth and the absence of significant side effects.

[0262] The invention further relates to a method for the treatment ofmammals, including humans, which are suffering from one of theabovementioned illnesses. The method is characterized in that atherapeutically active and pharmacologically effective and tolerableamount of one or more of the compounds according to the invention isadministered to the ill mammal.

[0263] The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

[0264] The invention also relates to the use of the compounds accordingto the invention for the production of medicaments which are employedfor the treatment and/or prophylaxis of the illnesses mentioned.

[0265] The invention furthermore relates to medicaments for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

[0266] Additionally, the invention relates to an article of manufacture,which comprises packaging material and a pharmaceutical agent containedwithin said packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterases of type 4 and 7 (PDE4/7), ameliorating thesymptoms of an PDE4- and/or PDE7-mediated disorder, and wherein thepackaging material comprises a label or package insert which indicatesthat the pharmaceutical agent is useful for preventing or treating PDE4-and/or PDE7-mediated disorders, and wherein said pharmaceutical agentcomprises one or more compounds of formula I according to the invention.The packaging material, label and package insert otherwise parallel orresemble what is generally regarded as standard packaging material,labels and package inserts for pharmaceuticals having related utilities.

[0267] The medicaments are prepared by processes which are known per seand familiar to the person skilled in the art. As medicaments, thecompounds according to the invention (=active compounds) are eitheremployed as such, or preferably in combination with suitablepharmaceutical auxiliaries and/or excipients, e.g. In the form oftablets, coated tablets, capsules, caplets, suppositories, patches (e.g.as TTS), emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95% and where, by theappropriate choice of the auxiliaries and/or excipients, apharmaceutical administration form (e.g. a delayed release form or anenteric form) exactly suited to the active compound and/or to thedesired onset of action can be achieved.

[0268] The person skilled in the art is familiar with auxiliaries orexcipients which are suitable for the desired pharmaceuticalformulations on account of his/her expert knowledge. In addition tosolvents, gel formers, ointment bases and other active compoundexcipients, for example antioxidants, dispersants, emulsifiers,preservatives, solubilizers, colorants, complexing agents or permeationpromoters, can be used.

[0269] The administration of the medicaments according to the inventionmay be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral and intravenous deliveryare preferred.

[0270] For the treatment of disorders of the respiratory tract, thecompounds according to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantagously of 2 to 6 μm.

[0271] Aerosol generation can be carried out, for example, bypressure-driven jet atomizers or ultrasonic atomizers, butadvantageously by propellant-driven metered aerosols or propellant-freeadministration of micronized active compounds from inhalation capsules.

[0272] Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

[0273] For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patent. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic deylces emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

[0274] For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosemedicaments which are suitable for topical application. For theproduction of the medicaments, the compounds according to the invention(=active compounds) are preferably mixed with suitable pharmaceuticalauxiliaries and further processed to give suitable pharmaceuticalformulations. Suitable pharmaceutical formulations are, for example,powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

[0275] The medicaments according to the invention are prepared byprocesses known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for PDE inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active com- pounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarly between0.1 and 3 mg per day. The customary dose in the case of systemic therapy(p.o. or i.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

[0276] Method for Measuring Inhibition of PDE4 and PDE7 Activities

[0277] The cDNA for PDE7A1 (Genebank Acc. No. L12052) was isolated,using RT-PCR, from total cellular RNA derived from the T cell lineCCRF-CEM and cloned into the cloning vector pCR2.1 (invitrogen,Groningen, NL) under standard conditions (the manufacturer'sinstructions). For expression in insect cells, the cDNA was subclonedinto the baculo expression vector pCRBac (invitrogen, Groningen, NL).The cDNA for PDE4D3 was a gift of Marco Conti (Stanford University,USA). The ORF (Genebank Acc. No. U50159) was cut from the original pCMV5vector with the restriction enzymes EcoRI and XbaI and subcloned in theexpression vector pBacPak9 (Clontech, Palo Alto).

[0278] The recombinant baculoylrus was prepared by means of homologousrecombination in SF9 insect cells. The expression plasmids werecotransfected with Bac-N-Blue (invitrogen, Groningen, NL) or Baculo-GoldDNA (Pharmingen, Hamburg) using a standard protocol (Pharmingen,Hamburg). Wt virus-free recombinant virus supernatants were selectedusing plaque assay methods. After that, high-titre virus supernatantswere prepared by amplifying 3 times. PDEs were expressed in SF21 cellsby infecting 2×10⁶ cells/ml with an MOI (multiplicity of infection)between 2 and 5 in serum-free SF900 medium (Life Technologies, Paisley,UK). The cells were cultured at 28° C. for 48 hours, after which theywere pelleted for 5-10 min at 1000 g and 4° C. In the case of PDE7A1cells were cultured in spinner flasks at a rotational speed of 75 rpm.

[0279] The SF21 insect cells were resuspended, at a concentration ofapprox. 10⁷ cells/ml, in ice-cold (4° C.) homogenization buffer (20 mMTris, pH 8.2, containing the following additions: 140 mM NaCl, 3.8 mMKCl, 1 mM EGTA, 1 mM MgCl₂, 1 mM β-mercaptoethanol, 2 mM benzamidine,0.4 mM Pefablock, 10 μM leupeptin, 10 μM pepstatin A, 5 μM trypsininhibitor) and disrupted by ultrasonication. The homogenate was thencentrifuged for 10 min at 1000×g and the supernatant was stored at −80°C. until subsequent use (see below). The protein content was determinedby the Bradford method (BioRad, Munich) using BSA as the standard.

[0280] PDE7A1 and PDE4D3 activities were inhibited by the said compoundsin a modified SPA (scintillation proximity assay) test, supplied byAmersham Pharmacia Biotech (see procedural instructions“phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090”), carriedout in 96-well microtitre plates (MTP's). The test volume is 100 μl andcontains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serumalbumin)/ml, 5 mM Mg²⁺, 0.5 μM cAMP (including about 50,000 cpm of[3H]cAMP), 2 μl of the respective substance dilution in DMSO andsufficient recombinant PDE (1000×g supernatant, see above) to ensurethat 15-20% of the cAMP is converted under the said experimentalconditions. After a preincubation of 5 min at 37° C., the reaction isstarted by adding the substrate (cAMP) and the assays are incubated fora further 15 min; after that, they are stopped by adding SPA beads (50μl). In accordance with the manufacturer's instructions, the SPA beadshad preylously been resuspended in water and then diluted 1:3 (v/v); thediluted solution also contains 3 mM IBMX. After the beads have beensedimented (>30 min), the MTP's are analyzed in commercially availablemeasuring appliances and the corresponding IC50 values of the compoundsfor the inhibition of PDE activities are determined from theconcentration-effect curves by means of non-linear regression.

[0281] The inhibitory values determined for the compounds according tothe invention follow from the following table A, in which the numbers ofthe compounds correspond to the numbers of the examples. TABLE AInhibition of PDE4 and PDE7 acitivity [measured as −logIC₅₀ (mol/l)]PDE4 PDE7 Compound −logIC₅₀ (mol/l) −logIC₅₀ (mol/l) 1 8.64 7.64 2 8.46.97 3 8.25 6.74 4 8.61 7.38 5 7.86 7.18 6 7.64 7.08 7 8.09 6.98 8 8.057.05 9 8.59 7.54 10 9.11 7.73 11 9.05 6.57 12 8.19 7.01 13 7.34 6.42 177.66 7.38 18 7.63 7.11

1. (Original) Compounds of formula I

in which R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine, R2 is fluorine, bromine orchlorine, R3 and R4 are both hydrogen or together form an additionalbond, R5 is R6, —C_(m)H_(2m)—R7, —C_(n)H_(2n)—C(O)R8, —CH(R9)₂,—C_(p)H_(2p)—Y-Aryl1, R12 or R26, in which R6 1-8C-alkyl,3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 3-7C-alkenyl, 3-7C-alkinyl,phenyl-3-4C-alkenyl, 7-10C-polycycloalkyl, naphthyl, pyridyl, pyrazinyl,pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl,isoquinolinyl, quinolinyl, indanyl, indazolyl, benzoxazolyl,benzothiazolyl, oxazolyl, thiazolyl, N-methylpiperidyl,tetrahydropyranyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)-benzoic acid,or an unsubstituted or by R61 and/or R62 substituted phenyl radical, inwhich R61 is hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, nitro, cyano, halogen,carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C-alkoxycarbonyl,hydroxy-1-4C-alkyl, amino, mono- or di-1-4C-alkylamino,1-4C-alkylcarbonylamino, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, aminosulfonyl, mono- ordi-1-4C-alkylaminosulfonyl, 4-methylphenylsulfonamido, imidazolyl;tetrazol-5-yl, 2-(1-4C-alkyl)tetrazol-5-yl or 2-benzyl-tetrazol-5-yl andR62 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen, R7 is hydroxyl,halogen, cyano, nitro, nitroxy(—O—NO₂), carboxyl, carboxyphenyloxy,phenoxy, 1-4C-alkoxy, 3-7C-cydoalkoxy, 3-7C-cycloalkylmethoxy,1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,amino, mono- or di-1-4C-alkylamino, or an unsubstituted or by R71 and/orR72 substituted piperidyl, piperazinyl, pyrrolidinyl or morpholinylradical, where R71 is hydroxyl, 1-4C-alkyl, hydroxy-1-4C-alkyl or1-4C-alkoxycarbonyl, and R72 is 1-4C-alkyl, carboxyl, aminocarbonyl or1-4C-alkoxycarbonyl, R8 is an unsubstituted or by R81 and/or R82substituted phenyl, naphthyl, phenanthrenyl or anthracenyl radical, inwhich R81 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy,carboxyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkyicarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,1-4C-alkylcarbonylamino, or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine, and R82 is hydroxyl, halogen,1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine, R9 is —C_(q)H_(2q)-phenyl, Y is abond or O (oxygen), Aryl1 is an unsubstituted phenyl, naphthyl, pyridyl,pyrazinyl, pyridazinyl, pyrimidinyl, quinazolinyl, quinoxalinyl,cinnolinyl, isoquinolyl, quinolyl, coumarinyl, benzimidazolyl,benzoxazolyl, benzothiazolyl, benzotriazolyl, N-benzosuccinimidyl,imidazolyl, pyrazolyl, oxazolyl, thiazolyl, furyl, thienyl, pyrrolyl, a2-(1-4C-alkyl)-thiazol-4-yl radical, or a phenyl radical substituted byR10 and/or R11, in which R10 is hydroxyl, halogen, nitro, cyano,1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, carboxyl,hydroxycarbonyl-1-4C-alkyl, 1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl,amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino,aminocarbonyl, mono- or di-1-4C-alkylamino-carbonyl, imidazolyl ortetrazolyl, and R11 is hydroxyl, halogen, nitro, 1-4C-alkyl or1-4C-alkoxy, m is an integer from 1 to 8, n is an integer from 1 to 4, pis an integer from 1 to 6, q is an integer from 0 to 2, R12 is a radicalof formula (a)

wherein R13 is —S(O)₂—R14, —S(O)₂—(CH₂)_(r)—R15, —(CH₂)_(s)—S(O)₂—R16,—C(O)R17, —C(O)—(CH₂)_(r)—R18, —(CH₂)_(s)—C(O)—R19, Hetaryl1, Aryl2 orAryl3-1-4C-alkyl, R14 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl,—N(R20)R21, phenyl or phenyl substituted by R22 and/or R23, R15 is—N(R20)R21, R16 is —N(R20)R21, R17 is 1-4C-alkyl,hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl,4-ethyl-piperazin-2,3-dion-1-yl, 2-oxo-imidazolidin-1-yl or —N(R20)R21,R18 is —N(R20)R21, R19 is —N(R20)R21, phenyl, phenyl substituted by R22and/or R23 and/or R24, R20 and R21 are independent from each otherhydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or phenyl,or R20 and R21 together and with inclusion of the nitrogen atom to whichthey are bonded, form a 4-morpholinyl-ring, 1-pyrrolidinyl-ring,1-piperidinyl-ring, 1-hexahydroazepino-ring or a 1-piperazinyl-ring offormula (b)

 wherein  R25 is pyrid-4-yl, pyrid4-ylmethyl, 1-4C-alkyl-dimethylamino,dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethylor tetrahydrofuran-2-ylmethyl, R22 is halogen, nitro, cyano, carboxyl,1-4C-alkyl, trifluoromethy, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino,mono-or di-1 4C-alkyiamino, aminocarbonyl 1-4C-alkylcarbonylamino ormono-or di-1-4C-alkyiaminocarbonyl, R23 is halogen, amino, nitro,1-4C-alkyl or 1-4C-alkoxy, R24 is halogen, Hetaryl1 is pyrimidin-2-yl,thieno-[2,3-d]pyrimidin-4-yl,1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl orfuranyl, Aryl2 is pyridyl, phenyl or phenyl substituted by R22 and/orR23, Aryl3 is pyridyl, phenyl, phenyl substituted by R22 and/or R23,2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl, r is aninteger from 1 to 4, s is an integer from 1 to 4, R26 is a radical offormula (c)

wherein R27 is —C(O)R28, —(CH₂)_(t)—C(O)R29, —(CH₂)_(u)R30, Aryl4,Hetaryl2, phenylprop-1-en-3-yl or 1-methylpiperidin-4-yl, R28 hydrogen,1-4C-alkyl, —OR31, furanyl, indolyl, phenyl, pyridyl, phenyl substitutedby R34 and/or R35 or pyridyl substituted by R36 and/or R37, R29 is—N(R32)R33, R30 is —N(R32)R33, tetrahydrofuranyl or pyridinyl, R31 is1-4C-alkyl, R32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, R33 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, or R32 and R33 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl4 isphenyl, pyridyl, pyrimidinyl, phenyl substituted by R34 and/or R35,pyridyl substituted by R36 and/or R37, R34 is halogen, nitro,1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R35 is halogen or1-4C-alkyl, R36 is halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy, R37 is halogen or 1-4C-alkyl, Hetaryl2 is indol-4-yl,2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl,3-phenyl-1,2,4-thiadiazol-5-yl or 3-o-tolyl-1,2,4-thiadiazol-5-yl, t isan integer from 1 to 4, u is an integer from 1 to 4, v is an integerfrom 1 to 2, X is —C(O)— or —S(O)₂—, and the salts of these compounds,with the proviso that the compound(cis)-4-(3-Chloro-4-methoxyphenyl)-2-cycloheptyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-oneis excluded.
 2. (original) Compounds of formula I according to claim 1in which R1 is methoxy or ethoxy, R2 is chlorine, bromine or fluorine R3and R4 together form an additional bond, R5 is R6, —C_(m)H_(2m)—R7,—C_(p)H_(2p)—Y-Aryl1, R12 or R26 in which R6 3-6C-cycloalkyl,3-7C-cycloalkylmethyl, quinoxalinyl, indazolyl, benzothiazolyl,6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,3-thiophen-2-yl[1,2,4]-thiadiazol-5-yl,1,1-dioxide-tetrabydrothiophen-3-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)-benzoic acid,or an unsubstituted or by R61 substituted phenyl radical, in which R61is 1-4C-alkyl, 1-4C-alkoxy, carboxyl or 1-4C-alkoxycarbonyl, R7 iscarboxyphenyloxy, Y is a bond, Aryl1 is imidazolyl, m is an integer from1 to 4, p is an integer from 1 to 4, R12 is a radical of formula (a)

wherein R13 is —S(O)₂—R14, —C(O)R17 or Aryl3-1-4C-alkyl, R14 is phenylor phenyl substituted by R22, R17 is 1-4C-alkyl, 2-oxo-imidazolidin-1-ylor —N(R20)R21, R20 and R21 are independent from each other 1-7C-alkyl,or R20 and R21 together and with inclusion of the nitrogen atom to whichthey are bonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-or 1-hexahydroazepino-ring, R22 is 1 4C-alkyl, Aryl3 is pyridyl, R26 isa radical of formula (c)

wherein R27 is —(CH₂)_(u)R30, R30 is —N(R32)R33, R32 is 1-4C-alkyl, R33is 1-4C-alkyl, or R32 and R33 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, u is aninteger from 1 to 4, v is 1, X is —C(O)—, and the salts of thesecompounds.
 3. (Original) Compounds of formula I according to claim 1 inwhich R1 is methoxy or ethoxy, R2 is chlorine, bromine or fluorine, R3and R4 together form an additional bond, R5 is1-(morpholin-4-yl-methanoylypiperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid,4-hydroxycarbonylphenyl or1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl, and the salts ofthese compounds.
 4. (Original) Compounds of formula I according to claim1 in which R1 is methoxy or ethoxy, R2 is chlorine, R3 and R4 togetherform an additional bond, R5 is1-(morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid,4-hydroxycarbonylphenyl or1-[1-[2-oxo-imidazolidin-1-yl)methanoyl]piperidin-4-yl, and the salts ofthese compounds.
 5. (Original) Compounds of formula I according to claim1 selected from(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-2-(1-Acetyl-piperidin-4-yl)-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-pyridin-4-ylmethyl-piperidin-4-yl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(6-methyl-3-trifluoromethyl-pyridin-2-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-2-Benzothiazol-6-yl-4-(3-chloro-4-methoxy-phenyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1-oxo-1,3-dihydro-isobenzofuran-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1H-indazol-5-yl)4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-cyclopentyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(4-imidazol-1-yl-butyl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-{4-[4-(3-Chloro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-butoxy}-benzoicacid, (cis)-4-[4-(3-Fluoro-4-methoxy-phenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl]-benzoic acid,(cis)-4-{4-(3-chloro-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzoicacid,(cis)-4-{4-(3-bromo-4-methoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-2H-phthalazin-2-yl}benzoicacid,(cis)-4-(3-chloro-4-methoxy-phenyl)-2-quinoxalin-2-yl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(3-thiophen-2-yl-[1,2,4]thiadiazol-5-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-(1,1-dioxo-tetrahydro-1l(6)-thiophen-3-yl)-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-ethoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-phenyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-{1-[1-(2-oxo-imidazolidin-1-yl)-methanoyl]-piperidin-4-yl}-4a,5,8,8a-tetrahydro-2H-phthalazin-1-one,and the salts of these compounds.
 6. (Original) Compounds of formula Iaccording to claim 1 in which R1 is 1-2C-alkoxy or 1-2C-alkoxy which iscompletely or predominantly substituted by fluorine, R2 is fluorine,bromine or chlorine, R3 and R4 are both hydrogen or together form anadditional bond, R5 is R6, —C_(m)H_(2m)—R7, —C_(n)H_(2n)—C(O)R8,—CH(R9)₂, —C_(p)H_(2p)—Y-Aryl1, R12 or R26, in which R6 1-8C-alkyl,3-10C-cycloalkyl, 3-7C-cycloalkylmethyl, 3-7C-alkenyl, 3-7C-alkinyl,phenyl-3-4C-alkenyl, 7-10C-polycycloalkyl, naphthyl, pyridyl, pyrazinyl,pyridazinyl, pyrimidyl, quinazolinyl, quinoxalinyl, cinnolinyl,isoquinolinyl, quinolinyl, indanyl, indazolyl, benzoxazolyl,benzothiazolyl, oxazolyl, thiazolyl, N-methylpiperidyl,tetrahydropyranyl, 6-methyl-3-trifluoromethyl-pyridin-2-yl,1,3,4-trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 4-(4-yl-but-1-oxy)-benzoic acid,or an unsubstituted or by R61 and/or R62 substituted phenyl radical, inwhich R61 is hydroxyl, 1-4C-alkyl, 1-4C-alkoxy, nitro, cyano, halogen,carboxyl, hydroxycarbonyl-1-4C-alkyl, 1-4C-alkoxycarbonyl,hydroxy-1-4C-alkyl, amino, mono- or di-14C-alkylamino,1-4C-alkylcarbonylamino, aminocarbonyl, mono- ordi-1AC-alkylaminocarbonyl, aminosulfonyl, mono- ordi-1-4C-alkylaminosulfonyl, 4-methylphenylsulfonamido, imidazolyl,tetrazol-5-yl, 2-(1-4C-alkyl)tetrazol-5-yl or 2-benzyl-tetrazol-5-yl andR62 is 1-4C-alkyl, 1-4C-alkoxy, nitro or halogen, R7 is hydroxyl,halogen, cyano, nitro, nitroxy(—O—NO₂), carboxyl, carboxyphenyloxy,phenoxy, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy,1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,amino, mono- or di-1-4C-alkylamino, or an unsubstituted or by R71 and/orR72 substituted piperidyl, piperazinyl, pyrrolidinyl or morpholinylradical, where R71 is hydroxyl, 1-4C-alkyl, hydroxy-1-4C-alkyl or1-4C-alkoxycarbonyl, and R72 is 1-4C-alkyl, carboxyl, aminocarbonyl or1-4C-alkoxycarbonyl, R8 is an unsubstituted or by R81 and/or R82substituted phenyl, naphthyl, phenanthrenyl or anthracenyl radical, inwhich R81 is hydroxyl, halogen, cyano, 1-4C-alkyl, 1-4C-alkoxy,carboxyl, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, and R82 ishydroxyl, halogen, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine, R9 is—C_(q)H_(2q)-phenyl, Y is a bond or O (oxygen), Aryl1 is anunsubstituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl,pyrimidinyl, quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl,quinolyl, coumarinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,benzotriazolyl, N-benzosuccinimidyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, furyl, thienyl, pyrrolyl, a 2-(1-4C-alkyl)-thiazol-4-ylradical, or a phenyl radical substituted by R10 and/or R11, in which R10is hydroxyl, halogen, nitro, cyano, 1-4C-alkyl, trifluoromethyl,1-4C-alkoxy, carboxyl, hydroxycarbonyl-1-4C-alkyl,1-4C-alkylcarbonyloxy, 1-4C-alkoxycarbonyl, amino, mono- ordi-1-4C-alkylamino, 1-4C-alkylcarbonylamino, aminocarbonyl, mono- ordi-1-4C-alkylamino-carbonyl, imidazolyl or tetrazolyl, and R11 ishydroxyl, halogen, nitro, I-4C-alkyl or 1-4C-alkoxy, m is an integerfrom 1 to 8, n is an integer from 1 to 4, p is an integer from 1 to 6, qis an integer from 0 to 2, R12 is a radical of formula (a)

wherein R13 is —S(O)₂—R14, —S(O)₂—(CH₂)_(r)—R15, —(CH₂)_(s)—S(O)₂—R16,—C(O)R17, —C(O)—(CH₂)_(r)—R18, —(CH₂)_(s)—C(O)—R19, Hetaryl1, Aryl2 orAryl3-1-4C-alkyl, R14 is 1-4C-alkyl, 5-dimethylaminonaphthalin-1-yl,—N(R20)R21, phenyl or phenyl substituted by R22 and/or R23, R15 is—N(R20)R21, R16 is —N(R20)R21, R17 is 1-4C-alkyl,hydroxycarbonyl-1-4C-alkyl, phenyl, pyridyl,4-ethyl-piperazin-2,3-dion-1-yl or —N(R20)R21, R18 is —N(R20)R21, R19 is—N(R20)R21, phenyl, phenyl substituted by R22 and/or R23 and/or R24, R20and R21 are independent from each other hydrogen, 1-7C-alkyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl or phenyl, or R20 and R21together and with inclusion of the nitrogen atom to which they arebonded, form a 4-morpholinyl-, 1-pyrrolidinyl-, 1-piperidinyl-,1-hexahydroazepino- or a 1-piperazinyl-ring of formula (b)

 wherein  R25 is pyrid-4-yl, pyrid-4-ylmethyl, 1-4C-alkyl-dimethylamino,dimethylaminocarbonylmethyl, N-methyl-piperidin-4-yl, 4-morpholino-ethylor tetrahydrofuran-2-ylmethyl, R22 is halogen, nitro, cyano, carboxyl,1-4C-alkyl, trifluoromethyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, amino,mono-or di-1-4C-alkylamino, aminocarbonyl 1-4C-alkylcarbonylamino ormono-or di-1-4C-alkylaminocarbonyl, R23 is halogen, amino, nitro,1-4C-alkyl or 1-4C-alkoxy, R24 is halogen, Hetaryl1 is pyrimidin-2-yl,thieno-[2,3-d]pyrimidin-4-yl,1-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4-yl, thiazolyl, imidazolyl orfuranyl, Aryl2 is pyridyl, phenyl or phenyl substituted by R22 and/orR23, Aryl3 is pyridyl, phenyl, phenyl substituted by R22 and/or R23,2-oxo-2H-chromen-7-yl or 4-(1,2,3-thiadiazol-4-yl)phenyl, r is aninteger from 1 to 4, s is an integer from 1 to 4, R26 is a radical offormula (c)

wherein R27 is —C(O)R28, —(CH₂)_(t)—C(O)R29, —(CH₂)_(u)R30, Aryl4,Hetaryl2, phenylprop-1-en-3-yl or 1-methyl-piperidin-4-yl, R28 hydrogen,1-4C-alkyl, -OR31, furanyl, indolyl, phenyl, pyridyl, phenyl substitutedby R34 and/or R35 or pyridyl substituted by R36 and/or R37, R29 is—N(R32)R33, R30 is —N(R32)R33, tetrahydrofuranyl or pyridinyl, R31 is1-4C-alkyl, R32 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl or3-7C-cycloalkylmethyl, R33 is hydrogen or 1-4C-alkyl, 3-7C-cycloalkyi or3-7C-cycloalkylmethyl, or R32 and R33 together and with inclusion of thenitrogen atom to which they are bonded, form a 4-morpholinyl-,1-pyrrolidinyl-, 1-piperidinyl- or 1-hexahydroazepinyl-ring, Aryl4 isphenyl, pyridyl, phenyl substituted by R34 and/or R35, pyridylsubstituted by R36 and/or R37, R34 is halogen, nitro, 1-4C-alkyl,trifluoromethyl or 1-4C-alkoxy, R35 is halogen or 1-4C-alkyl, R36 ishalogen, nitro, 1 4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R37 ishalogen or 1-4C-alkyl, Hetaryl2 is indol-4-yl, 2-methyl-quinolin-4-yl,5-chloro-6-oxo-1-phenyl-1,6-dihydro-pyridazin-4-yl or3-phenyl-1,2,4-thiadiazol-5-yl, t is an integer from 1 to 4, u is aninteger from 1 to 4, v is an integer from 1 to 2, X is —C(O)— or—S(O)₂—, and the salts of these compounds, with the proviso that thecompound(cis)-4-(3-Chloro-4-methoxy-phenyl)-2-cycloheptyl-4a,5,8,8a-tetrahydro-2H-phthalazin-1-oneis excluded.
 7. (Original) Compounds of formula I according to claim 1in which R1 is methoxy or ethoxy, R2 is chlorine, R3 and R4 togetherform an additional bond, R5 is1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,quinoxalin-2-yl, 6-methyl-3-trifluoromethyl-pyridin-2-yl, 1,3,4trimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl, phenyl,3-thiophen-2-yl[1,2,4]thiadiazol-5-yl,1,1-dioxide-tetrahydrothiophen-3-yl, 2-benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid orhydroxycarbonylphen-4-yl, and the salts of those compounds. 8.(Original) Compounds of formula I according to claim 1 in which R1 ismethoxy, R2 is chlorine, R3 and R4 together form an additional bond, R5is 1-(1-morpholin-4-yl-methanoyl)-piperidin-4-yl,1-(toluene-4-sulfonyl)-piperidin-4-yl, 1-acetyl-piperidin-4-yl,1-(pyridin-4-ylmethyl)-piperidin-4-yl,4-{1-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-methanoyl}-phenyl,6-methyl-3-trifluoromethyl-pyridin-2-yl, 2-benzothiazol-6-yl,1-oxo-1,3-dihydro-isobenzofuran-5-yl, 1H-indazol-5-yl, cyclopentyl,4-imidazol-1-yl-butyl, 4-(4-yl-but-1-oxy)-benzoic acid orhydroxycarbonylphen-4-yl, and the salts of those compounds. 9.(Currently Amended) Compounds of Formula I according to claim 1 in whichthe hydrogen atoms in the positions 4a and 8a are cis-configurated. 10.(Currently Amended) Compounds of Formula I according to claim 1 in whichthe absolute configuration (according to the rules of Cahn, ingold andPrelog) is S in the position 4a and R in the position 8a.
 11. (Currentlyamended) A method of treating a disease or disorder in a patientcomprising administering to a patient in need thereof a compound offormula I according to claim 1 .
 12. (Currently amended) Apharmaceutical composition comprising one or more compounds of formula Iaccording to claim 1 together with one or more pharmaceuticallyacceptable auxiliaries and/or carrier materials.
 13. (Currently amended)A method of treating an airway disorder in a patient comprisingadministering to a patient in need thereof an effective amount of acompound of formula I according to claim 1.